bims-medica 2024-09-15 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–09–15
24 papers selected by
Brett Chrest, East Carolina University

Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.
Relapse and resistance in acute myeloid leukemia post venetoclax: improving second lines therapy and combinations.
Synergistic and antagonistic drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines.
Beyond glucose: The crucial role of redox signaling in β-cell metabolic adaptation.
A genetically encoded fluorescent reporter for polyamines.
Starvation Ketoacidosis on the Acute Medical Take: An Easily Missed Complication of the Keto Diet.
Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
Advances in the pathogenesis of FLT3-mutated acute myeloid leukemia and targeted treatments.
Oligodendroglial fatty acid metabolism as a central nervous system energy reserve.
Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.
Modern Perspective of Lactate Metabolism.
Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.
Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.
IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.
Strategies to Maintain Redox Homeostasis in Yeast Cells with Impaired Fermentation-Dependent NADPH Generation.
Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
Role of AMPK in Atrial Metabolic Homeostasis and Substrate Preference.
Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain.
Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate.
Breast Cancer With Release of Tumor Cells in Peripheral Blood Mimicking Acute Myeloid Leukemia.
Early drivers of clonal hematopoiesis shape the evolutionary trajectories of de novo acute myeloid leukemia.
Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.
Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers.

Nat Metab. 2024 Sep 09.

Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.

Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.

While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present 13C-SpaceM, a method for spatial single-cell isotope tracing that extends the previously published SpaceM method with detection of 13C6-glucose-derived carbons in esterified fatty acids. We validated 13C-SpaceM on spatially heterogeneous models using liver cancer cells subjected to either normoxia-hypoxia or ATP citrate lyase depletion. This revealed substantial single-cell heterogeneity in labelling of the lipogenic acetyl-CoA pool and in relative fatty acid uptake versus synthesis hidden in bulk analyses. Analysing tumour-bearing brain tissue from mice fed a 13C6-glucose-containing diet, we found higher glucose-dependent synthesis of saturated fatty acids and increased elongation of essential fatty acids in tumours compared with healthy brains. Furthermore, our analysis uncovered spatial heterogeneity in lipogenic acetyl-CoA pool labelling in tumours. Our method enhances spatial probing of metabolic activities in single cells and tissues, providing insights into fatty acid metabolism in homoeostasis and disease.

DOI: https://doi.org/10.1038/s42255-024-01118-4
Cancer Lett. 2024 Sep 11. pii: S0304-3835(24)00637-2. [Epub ahead of print] 217242

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase.

Katerina Hlozkova, Maryna Vasylkivska, Adam Boufersaoui, Bryan Marzullo, Matus Kolarik, Natividad Alquezar-Artieda, Mehak Shaikh, Fatemeh Alaei Faradonbeh, Marketa Zaliova, Martina Zwyrtkova, Violeta Bakardijeva-Mihaylova, Meritxell Alberich-Jorda, Jan Trka, Daniel A Tennant, Julia Starkova.

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

DOI: https://doi.org/10.1016/j.canlet.2024.217242
Expert Rev Hematol. 2024 Sep 13. 1-17

Relapse and resistance in acute myeloid leukemia post venetoclax: improving second lines therapy and combinations.

Rabia Shahswar, Arnold Ganser.

   INTRODUCTION: The combined use of the BCL-2 inhibitor venetoclax with azacitidine now is the standard of care for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy with outcomes exceeding those achieved with hypomethylating agents alone. Venetoclax in combination with intensive chemotherapy is also increasingly used both as frontline as well as salvage therapy. However, resistance to and relapse after venetoclax-based therapies are of major concern and outcomes after treatment failure remain poor.
AREAS COVERED: A comprehensive search was performed using PubMed database (up to April 2024). Studies evaluating venetoclax-based combination treatments in AML and studies assessing markers of response and resistance to venetoclax were investigated. We summarize the status of venetoclax-based therapies in the frontline and relapsed/refractory setting with focus on the main mechanisms of resistance to BCL-2 inhibition. Further, strategies to overcome resistance including combinatorial regimens of hypomethylating agent (HMA) + venetoclax + inhibitors targeting actionable mutations like IDH1/2 or FLT3-ITD and the introduction of novel agents like menin-inhibitors are addressed.
EXPERT OPINION: Although venetoclax is reshaping the treatment of unfit and fit AML patients, prognosis of patients after HMA/VEN failure remains dismal, and strategies to abrogate primary and secondary resistance are an unmet clinical need.

Keywords:  Acute myeloid leukemia; combined targeted therapy; hypomethylating agent; resistance; venetoclax

DOI:  https://doi.org/10.1080/17474086.2024.2402283
Res Sq. 2024 Aug 26. pii: rs.3.rs-4159724. [Epub ahead of print]

Synergistic and antagonistic drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines.

Fatma Neslihan Kalkan, Muhammed Sadik Yildiz, N Ezgi Wood, Michael Farid, Melissa McCoy, Milo Lin, Chengcheng Zhang, Bruce Posner, Stephen S Chung, Erdal Toprak.

Acute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Its heterogeneity, both between patients and within the same patient, is often a factor contributing to poor treatment outcomes. Despite advancements in AML biology and medicine in general, the standard AML treatment, the combination of cytarabine and daunorubicin, has remained the same for decades. Combination drug therapies are proven effective in achieving targeted efficacy while minimizing drug dosage and unintended side effects, a common problem for older AML patients. However, a systematic survey of the synergistic potential of drug-drug interactions in the context of AML pathology is lacking. Here, we examine the interactions between 15 commonly used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib and venetoclax, recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine, a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Importantly, these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary significantly depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones. Our findings provide a preclinical survey of drug-drug interactions, revealing the complexity of the problem.

DOI: https://doi.org/10.21203/rs.3.rs-4159724/v1
Metabolism. 2024 Sep 09. pii: S0026-0495(24)00254-3. [Epub ahead of print] 156027

Beyond glucose: The crucial role of redox signaling in β-cell metabolic adaptation.

Blanka Holendová, Barbora Šalovská, Štěpánka Benáková, Lydie Plecitá-Hlavatá.

   OBJECTIVE: Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health.
METHODS: We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells.
RESULTS: Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation.
CONCLUSIONS: Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.

Keywords:  Glucose; Pancreatic β-cells; Posttranslational modifications; ROS; Redox proteomics; Redox signaling

DOI:  https://doi.org/10.1016/j.metabol.2024.156027
bioRxiv. 2024 Aug 26. pii: 2024.08.24.609500. [Epub ahead of print]

A genetically encoded fluorescent reporter for polyamines.

Pushkal Sharma, Colin Y Kim, Heather R Keys, Shinya Imada, Alexander B Joseph, Luke Ferro, Tenzin Kunchok, Rachel Anderson, Omer H Yilmaz, Jing-Ke Weng, Ankur Jain.

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for genetic Parkinson's disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.

DOI: https://doi.org/10.1101/2024.08.24.609500
Eur J Case Rep Intern Med. 2024 ;11(9): 004830

Starvation Ketoacidosis on the Acute Medical Take: An Easily Missed Complication of the Keto Diet.

Ayesha Shaikh, David M Williams, Jeffrey W Stephens, Rhodri Edwards.

  Starvation ketoacidosis represents one of the three forms of metabolic acidosis caused by the accumulation of ketone bodies within the blood stream. It can be easily missed in patients who present acutely and are found to have an unexplained or profound metabolic acidosis. Here, we present a life-threatening case of severe ketoacidosis in a breast-feeding mother without diabetes who was on a strict ketogenic diet. Although a ketogenic diet has been previously considered to be safe in non-pregnant individuals, its safety in breast-feeding mothers in the post-partum period is less known and may be associated with greater harm. Health professionals and mothers should be aware of the potential risks associated with a strict ketogenic diet when combined with breast-feeding, especially in the earlier stages of the post-partum period. Prompt investigation, diagnosis and immediate management is vital to avoid life-threatening complications. We report a case admitted on the acute medical take with starvation ketoacidosis associated with ketogenic diet and adequate calorie consumption who was breast-feeding at the time of admission.
LEARNING POINTS: Always check ketones in patients with an unexplained metabolic acidosis; there can be overlap between starvation, alcohol-related and lactic acidosis.Management of starvation ketoacidosis is often empirical, involving close monitoring of fluid status and electrolytes.Clinicians should discuss the risk of ketoacidosis associated with the ketogenic diet in women who plan to breast-feed and lose weight following pregnancy.

Keywords:  Ketoacidosis; keto diet; weight-loss diet

DOI:  https://doi.org/10.12890/2024_004830
J Lipid Res. 2024 Sep 06. pii: S0022-2275(24)00146-9. [Epub ahead of print] 100641

Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.

Julia A Pinette, Jacob W Myers, Woo Yong Park, Heather G Bryant, Alex M Eddie, Genesis A Wilson, Claudia Montufar, Zayedali Shaikh, Zer Vue, Elizabeth R Nunn, Ryoichi Bessho, Matthew A Cottam, Volker H Haase, Antentor O Hinton, Jessica B Spinelli, Jean-Philippe Cartailler, Elma Zaganjor.

  A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.

Keywords:  adipocytes; adipogenesis; fatty acid oxidation; lipid droplets; metabolism; nucleotides; purine; pyrimidine

DOI:  https://doi.org/10.1016/j.jlr.2024.100641
Curr Opin Oncol. 2024 Aug 27.

Advances in the pathogenesis of FLT3-mutated acute myeloid leukemia and targeted treatments.

Serena Travaglini, Carmelo Gurnari, Tiziana Ottone, Maria Teresa Voso.

PURPOSE OF REVIEW: FLT3 mutations are among the most common myeloid drivers identified in adult acute myeloid leukemia (AML). Their identification is crucial for the precise risk assessment because of the strong prognostic significance of the most recurrent type of FLT3 alterations, namely internal tandem duplications (ITDs). Recent advances in the pathogenesis and biology of FLT3-mutated AML have opened an opportunity for development and application of selective inhibition of FLT3 pathway.
RECENT FINDINGS: In the last decade, at least three targeted treatments have been approved by regulatory agencies and several others are currently under investigations. Here, we review the latest advance in the role of FLT3 mutations in AML, providing an outline of the available therapeutic strategies, their mechanisms of actions and of resistance, as well as routes for potential improvement.
SUMMARY: The availability of FLT3 inhibitors has improved outcomes in AML harboring such mutations, currently also reflected in disease stratification and recommendations. Newer inhibitors are under investigations, and combinations with chemotherapy or other targeted treatments are being explored to further improve disease outcomes.

DOI: https://doi.org/10.1097/CCO.0000000000001094
Nat Neurosci. 2024 Sep 09.

Oligodendroglial fatty acid metabolism as a central nervous system energy reserve.

Ebrahim Asadollahi, Andrea Trevisiol, Aiman S Saab, Zoe J Looser, Payam Dibaj, Reyhane Ebrahimi, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Olaf Jahn, Jun Yup Lee, Anthony S Don, Michelle-Amirah Khalil, Karsten Hiller, Myriam Baes, Bruno Weber, E Dale Abel, Andrea Balabio, Brian Popko, Celia M Kassmann, Hannelore Ehrenreich, Johannes Hirrlinger, Klaus-Armin Nave.

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.

DOI: https://doi.org/10.1038/s41593-024-01749-6
Cancer Res. 2024 Sep 12.

Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.

Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang.

Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating pre-leukemic clones, here we used a conditional Runx1::Runx1t1 knock-in mouse model to evaluate pre-leukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these pre-leukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3861
Physiol Res. 2024 Aug 31. 73(4): 499-514

Modern Perspective of Lactate Metabolism.

J Vavřička, P Brož, D Follprecht, J Novák, A Kroužecký.

Once considered a metabolic waste product, today it is considered an important signaling molecule continuously forming under aerobic conditions. Lactate, a molecule primarily known as a byproduct of glycolysis, has gained importance in recent years due to its multifaceted role in various biological processes. Misconceptions surrounding lactate have persisted for centuries, especially the belief that elevated lactate levels were solely a result of low oxygen levels shaped early understanding. However, current research challenges this view and expands our comprehension of lactate's various roles. Unfortunately, despite all of the mentioned above lactate is rooted in modern society as a deterrent word and many people do not know its value in the human body, let alone clinical implementations or physical performance. The main goal of this review is to refresh current knowledge regarding lactate research and spread the overall information among a professional society. Key words: Lactate, Lactate metabolism, Lactic acid, Disease metabolism, Lactate shuttle.
EMBO Rep. 2024 Sep 13.

Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice.

Guoli Hu, Yilin Yu, Yinshi Ren, Robert J Tower, Guo-Fang Zhang, Courtney M Karner.

  Osteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.

Keywords:  Amino Acids; Glutaminolysis; Nucleotides; Osteoclast; Osteoporosis

DOI:  https://doi.org/10.1038/s44319-024-00255-x
FEBS Lett. 2024 Sep 11.

Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.

Caroline Harter, Frédéric Melin, Franziska Hoeser, Petra Hellwig, Daniel Wohlwend, Thorsten Friedrich.

  Respiratory complex I is a central metabolic enzyme coupling NADH oxidation and quinone reduction with proton translocation. Despite the knowledge of the structure of the complex, the coupling of both processes is not entirely understood. Here, we use a combination of site-directed mutagenesis, biochemical assays, and redox-induced FTIR spectroscopy to demonstrate that the quinone chemistry includes the protonation and deprotonation of a specific, conserved aspartic acid residue in the quinone binding site (D325 on subunit NuoCD in Escherichia coli). Our experimental data support a proposal derived from theoretical considerations that deprotonation of this residue is involved in triggering proton translocation in respiratory complex I.

Keywords:  Escherichia coli; NADH dehydrogenase; NADH:quinone oxidoreductase; iron–sulfur cluster; proton‐coupled electron transfer; quinone reduction; redox‐induced FTIR spectroscopy; site‐directed mutagenesis

DOI:  https://doi.org/10.1002/1873-3468.15013
Mol Med. 2024 Sep 10. 30(1): 143

IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.

Sung Woo Lee, Soyoon Kim, Bokyung Kim, Jung Bae Seong, Young-Ho Park, Hong Jun Lee, Dong Kyu Choi, Eunbyul Yeom, Dong-Seok Lee.

   BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown.
METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified.
RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition.
CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.

Keywords:  Cancer; Isocitrate dehydrogenase 2; Macrophage polarization; Mitochondria; Tumor microenvironment

DOI:  https://doi.org/10.1186/s10020-024-00911-x
Int J Mol Sci. 2024 Aug 27. pii: 9296. [Epub ahead of print]25(17):

Strategies to Maintain Redox Homeostasis in Yeast Cells with Impaired Fermentation-Dependent NADPH Generation.

Magdalena Kwolek-Mirek, Roman Maslanka, Sabina Bednarska, Michał Przywara, Kornelia Kwolek, Renata Zadrag-Tecza.

  Redox homeostasis is the balance between oxidation and reduction reactions. Its maintenance depends on glutathione, including its reduced and oxidized form, GSH/GSSG, which is the main intracellular redox buffer, but also on the nicotinamide adenine dinucleotide phosphate, including its reduced and oxidized form, NADPH/NADP+. Under conditions that enable yeast cells to undergo fermentative metabolism, the main source of NADPH is the pentose phosphate pathway. The lack of enzymes responsible for the production of NADPH has a significant impact on yeast cells. However, cells may compensate in different ways for impairments in NADPH synthesis, and the choice of compensation strategy has several consequences for cell functioning. The present study of this issue was based on isogenic mutants: Δzwf1, Δgnd1, Δald6, and the wild strain, as well as a comprehensive panel of molecular analyses such as the level of gene expression, protein content, and enzyme activity. The obtained results indicate that yeast cells compensate for the lack of enzymes responsible for the production of cytosolic NADPH by changing the content of selected proteins and/or their enzymatic activity. In turn, the cellular strategy used to compensate for them may affect cellular efficiency, and thus, the ability to grow or sensitivity to environmental acidification.

Keywords:  6-phosphogluconate dehydrogenase; GSH/GSSG ratio; NADPH generation; NADPH/NADP+ ratio; acetic acid; aldehyde dehydrogenase 6; glucose-6-phosphate dehydrogenase; pH homeostasis; redox homeostasis; yeast

DOI:  https://doi.org/10.3390/ijms25179296
J Cell Physiol. 2024 Sep 08. e31417

Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.

Salvatore Cortellino, Margherita D'Angelo, Massimiliano Quintiliani, Antonio Giordano.

  Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.

Keywords:  cachexia; cancer metabolism; detary interventions; inflammation; malnutrition

DOI:  https://doi.org/10.1002/jcp.31417
bioRxiv. 2024 Aug 30. pii: 2024.08.29.608789. [Epub ahead of print]

Role of AMPK in Atrial Metabolic Homeostasis and Substrate Preference.

Zeren Toksoy, Yina Ma, Leigh Goedeke, Wenxue Li, Xiaoyue Hu, Xiaohong Wu, Marine Cacheux, Yansheng Liu, Fadi G Akar, Gerald I Shulman, Lawrence H Young.

Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), induces atrial remodeling culminating in atrial fibrillation in mice, implicating AMPK signaling in the maintenance of atrial electrical and structural homeostasis. However, atrial substrate preference for mitochondrial oxidation and the role of AMPK in regulating atrial metabolism are unknown. Here, using LC-MS/MS methodology combined with infusions of [ 13 C 6 ]glucose and [ 13 C 4 ]β-hydroxybutyrate in conscious mice, we demonstrate that conditional deletion of atrial AMPK catalytic subunits shifts mitochondrial atrial metabolism away from fatty acid oxidation and towards pyruvate oxidation. LC-MS/MS-based quantification of acyl-CoAs demonstrated decreased atrial tissue content of long-chain fatty acyl-CoAs. Proteomic analysis revealed a broad downregulation of proteins responsible for fatty acid uptake (LPL, CD36, FABP3), acylation and oxidation. Atrial AMPK deletion reduced expression of atrial PGC1-α and downstream PGC1-α/PPARα/RXR regulated gene transcripts. In contrast, atrial [ 14 C]2-deoxyglucose uptake and GLUT1 expression increased with fasting in mice with AMPK deletion, while the expression of glycolytic enzymes exhibited heterogenous changes. Thus, these results highlight the crucial homeostatic role of AMPK in the atrium, with loss of atrial AMPK leading to downregulation of the PGC1-α/PPARα pathway and broad metabolic reprogramming with a loss of fatty acid oxidation, which may contribute to atrial remodeling and arrhythmia.

DOI: https://doi.org/10.1101/2024.08.29.608789
Cancer Cell. 2024 Sep 12. pii: S1535-6108(24)00314-3. [Epub ahead of print]

Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain.

Siting Gan, Danilo G Macalinao, Sayyed Hamed Shahoei, Lin Tian, Xin Jin, Harihar Basnet, Catherine Bibby, James T Muller, Pranita Atri, Evan Seffar, Walid Chatila, Ali Karacay, Pharto Chanda, Anna-Katerina Hadjantonakis, Nikolaus Schultz, Edi Brogi, Tejus A Bale, Nelson S Moss, Rajmohan Murali, Dana Pe'er, Joan Massagué.

  Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.

Keywords:  brain metastasis; breast cancer; extracellular matrix; microglia; tumor architecture; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2024.08.015
Front Nutr. 2024 ;11 1443483

Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate.

Sujin Kim, Dong-Ho Park, Sohee Moon, Bonsang Gu, Keren Esther Kristina Mantik, Hyo-Bum Kwak, Ji-Kan Ryu, Ju-Hee Kang.

   Introduction: Despite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both in vitro and in vivo models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.
Methods: We evaluated the effects of β-HB on fat browning, thermogenesis, lipid accumulation, adipokine expression, and mitochondrial biogenesis by treating mature 3T3-L1 adipocytes with sodium β-HB for 24 h or by continuously exposing preadipocytes to β-HB during the 8-day differentiation process. Male Sprague Dawley rats were divided into control, exercise only (EX), ketogenic diet only (KD), and combined exercise and ketogenic diet (KE) groups for an 8-week intervention involving diet and/or exercise. After intervention, we evaluated WAT histology, plasma lipids and adipokines, and the expression of markers related to fat browning, thermogenesis and mitochondrial biogenesis in WAT of rats.
Results: In our adipocyte culture experiments, β-HB reduced intracellular lipid accumulation by enhancing lipolysis and stimulated the expression of thermogenic and fat browning genes like uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), and adipokines such as fibroblast growth factor 21 (FGF21) and Fibronectin type III domain-containing protein 5 (FDNC5). Additionally, β-HB activated the AMPK-SIRT1-PGC-1α pathway, with UCP1 and PRDM16 upregulation mediated by β-HB intracellular action and SIRT1 activity. In animal experiments, KE group raised β-HB levels, decreasing body weight and blood lipids. KD with EX promoted WAT browning possibly via AMPK-SIRT1-PGC-1α, augmenting PRDM16, UCP1, FGF21, and FNDC5 expression.
Conclusion: β-HB induction via KD and/or EX shows potential in promoting WAT browning by activating mitochondrial biogenesis, lipolysis, and thermogenesis, suggesting that dietary and physical intervention inducing β-HB may benefit metabolic health.

Keywords:  adipokine; beta-hydroxybutyrate; exercise; fat browning; ketogenic diet; mitochondrial biogenesis

DOI:  https://doi.org/10.3389/fnut.2024.1443483
J Hematol. 2024 Aug;13(4): 168-173

Breast Cancer With Release of Tumor Cells in Peripheral Blood Mimicking Acute Myeloid Leukemia.

Arianna Gatti, Bruno Brando, Irene Cuppari, Nadia Viola, Lorenzo Brunetti, Michela Sampaolo, Sonia More, Doriana Morichetti, Laura Corvatta.

  A 75-year-old woman with a history of lobular breast adenocarcinoma treated with mastectomy and radiotherapy in 2021 and on maintenance hormone therapy, presented with asthenia and tremors. Laboratory tests showed leucocytosis, anemia and low platelet count, with increased serum calcium, lactate dehydrogenase and indirect bilirubin levels. Haptoglobin was decreased and renal function was normal. Peripheral blood smear showed red cell anisocytosis, many schistocytes and immature granulocytes. Furthermore, 15% of white cells displayed large size and atypical morphology. A macroangiopathic hemolytic anemia (MAHA) related to a de novo or recurring cancer was hypothesized, and total body computed tomography (CT) and 18F-FDG positron emission tomography (PET)/CT were undertaken. Only a slight FDG uptake was demonstrated in the spine, attributable to a reactive bone marrow due to MAHA. Then, to rule out a MAHA related to acute leukemia, a bone marrow aspirate and trephine biopsy were performed, with an extensive cell immunophenotyping. The first myeloid flow cytometry (FC) panel evidenced a large volume population of about 20%, expressing CD117 but negative for CD45 and CD34. All myeloid markers were negative. A more extensive panel was then used, including plasma cell and erythroid markers. Interestingly, the abnormal population resulted positive for CD138 and CD71 with negativity for CD38. A recent study reported that besides CD45 negativity, non-hematological neoplasms frequently express CD56, CD117, or CD138. Therefore, a panel for non-hematological markers including epithelial cell adhesion molecule (EpCAM) was carried out. This population resulted EpCAM positive and also expressed CD9, a breast cancer prognostic marker. Bone marrow smears revealed the presence of the same cells, and the immunohistochemistry analysis of bone marrow biopsy demonstrated the massive infiltration of breast cancer cells, expressing all epithelial markers identified at diagnosis. The FC analysis of the peripheral blood allowed the rapid characterization of a non-hematological neoplastic cell population, circulating at unusually high frequency and mimicking an acute myeloid leukemia. The FC detection of CD45-negative cell populations in peripheral blood, bone marrow or lymph node aspirate should prompt the setup of an immunophenotyping panel including EpCAM, CD9, CD56 and CD117, to allow for a rapid and accurate identification of ectopic malignant epithelial cells.

Keywords:  Breast cancer; EpCAM; Flow cytometry; Immunophenotyping; Macroangiopathic hemolytic anemia

DOI:  https://doi.org/10.14740/jh1259
medRxiv. 2024 Sep 01. pii: 2024.08.31.24312756. [Epub ahead of print]

Early drivers of clonal hematopoiesis shape the evolutionary trajectories of de novo acute myeloid leukemia.

Ryan D Chow, Priya Velu, Safoora Deihimi, Jonathan Belman, Angela Youn, Nisargbhai Shah, Selina M Luger, Martin P Carroll, Jennifer Morrissette, Robert L Bowman.

Mutations commonly found in AML such as DNMT3A , TET2 and ASXL1 can be found in the peripheral blood of otherwise healthy adults - a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy. Meanwhile, later mutations in genes such as NPM1 and FLT3 , have been shown to contract at remission and in the case of FLT3 often are absent at relapse. We sought to understand how early CH mutations influence subsequent evolutionary trajectories throughout remission and relapse in response to induction chemotherapy. Here, we assembled a retrospective cohort of patients diagnosed with de novo AML at our institution that underwent genomic sequencing at diagnosis as well as at the time of remission and/or relapse (total n = 182 patients). Corroborating prior studies, FLT3 and NPM1 mutations were generally eliminated at the time of cytologic complete remission but subsequently reemerged upon relapse, whereas DNMT3A , TET2 and ASXL1 mutations often persisted through remission. Early CH-related mutations exhibited distinct constellations of co-occurring genetic alterations, with NPM1 and FLT3 mutations enriched in DNMT3A mut AML, while CBL and SRSF2 mutations were enriched in TET2 mut and ASXL1 mut AML, respectively. In the case of NPM1 and FLT3 mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.
Key Points: DNMT3A , TET2 and ASXL1 mutations persist through AML-directed therapy Distinct CH-related mutations shape the evolutionary trajectories of AML from diagnosis through relapse.

DOI: https://doi.org/10.1101/2024.08.31.24312756
Int J Mol Sci. 2024 Sep 04. pii: 9581. [Epub ahead of print]25(17):

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Lizhen Zhao, Hongbo Chen, Fengli Lan, Jinjin Hao, Wenzhi Zhang, Ying Li, Yuhong Yin, Minchun Huang, Xiaoyan Wu.

  Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

Keywords:  FLT3 mutation; acute lymphoblastic leukemia; acute myeloid leukemia; clinical features; gene expression; pediatric; prognosis

DOI:  https://doi.org/10.3390/ijms25179581
Curr Heart Fail Rep. 2024 Sep 07.

Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers.

Michael W Foster, Joshua M Riley, Praneet C Kaki, Amine Al Soueidy, Ehson Aligholiazadeh, J Eduardo Rame.

   PURPOSE OF REVIEW: The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression.
RECENT FINDINGS: Recent insights into myocardial metabolism shed light on the heart's response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure. Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure.

Keywords:  Biomarkers; Cardiomyopathy; Heart failure; Ketone bodies; Myocardial metabolism

DOI:  https://doi.org/10.1007/s11897-024-00678-6